The rapid mutability of HIV-1 has thwarted attempts to create a universal HIV-1 therapeutic immunogenic composition and prophylactic immunogenic composition. However, a transactivating protein termed Tat, which is encoded by HIV-1, secreted by HIV-1 infected cells, and taken up by uninfected CD4+ T cells, is a necessary prerequisite for large scale HIV-1 replication. Resting CD4+ T cells, the main body “tissue” sustaining HIV-1 replication, do not permit HIV-1 replication and Tat activation renders them permissive. Thus, circulating Tat protein presents a promising target for immunological interdiction of an obligatory pathway needed for maintenance of HIV-1 viremia.
The tat gene and its protein have been sequenced and examined for involvement in proposed treatments of HIV (see, e.g., the documents cited in U.S. Pat. No. 6,525,179). Uptake of Tat by cells is very strong, and has been reported as mediated by a short basic sequence of the protein (S. Fawell et al., 1994 Proc. Natl. Acad. Sci., USA, 91:664-668). Prior scientific publications and patent publications by the present inventor established that, although the amino acid sequence of Tat is highly variable, Epitope 1, the immunodominant B cell epitope of Tat, spanning amino acids 4-16, is largely conserved, showing fourfold variation at position 7 (Arg, Lys, Asn or Ser), twofold variation at position 9 (Glu or Asp) and twofold variation at position 12 (Lys or Asn). See, e.g., G. Goldstein, 1996 Nature Med., 2:960; G. Goldstein, 2000 Vaccine, 18:2789; International Patent Publication No. WO 95/31999, published Nov. 30, 1995; International Patent Publication No. WO 99/02185, published Jan. 21, 1999; International Patent Publication No. WO 01/82944, published Nov. 8, 2001; U.S. Pat. Nos. 5,891,994; 6,193,981; 6,399,067; 6,524,582; and 6,525,179; US Published Patent Application Nos. US 2003/0,166,832 and US 2003/0,180,326). Other investigators have subsequently noted some of these variabilities in Tat sequences. See, e.g., Tikhonov et al, 2003 J. Virol., 77(5):3157-3166; Ruckwardt et al, 2004 J. Virol., 78(23):13190-13196; and related International Publications WO2005/062871 and WO2004/056316, among others.
Both monoclonal and polyclonal antibodies to Tat protein have been produced in animals and shown to block uptake of Tat protein in vitro and such monoclonal or polyclonal antibodies to Tat protein added to tissue culture medium have attenuated HIV-1 infection in vitro (see, e.g., documents cited in U.S. Pat. No. 6,524,582). Compositions formed of combinations of these antibodies, particularly combinations of an antibody to one Epitope 1 variant with one or more antibodies that each binds a different Epitope 1 variant, are able to bind a large number of Tat variant sequences characteristic of the multiple strains and subtypes of HIV-1, both B and non-B clades. These antibody compositions are designed to passively immunize a subject, i.e., to inhibit HIV-1 infectivity during initial infection and/or lower viral load post sero-conversion, thus delaying progression to AIDS. Further, these resulting compositions or mixtures of such anti-Tat antibodies are treatments for many strains and subtypes of the virus, thus obviating the need for different, and strain-specific, therapeutic agents. Much work is ongoing in the development of a variety of passive immunization compositions for the treatment of HIV-1 infection.
Active immunization, in which a composition induces anti-Tat antibodies in the host, offers an alternative approach, both for therapy and for prophylaxis. Such immunization has been proposed by the inventor's own publications, as well as by others. However, to date, there remains a need in the art for new and useful compositions and methods for generating and using “universal” HIV-1 therapeutic immunogenic compositions and prophylactic immunogenic compositions that are capable of inducing an immune response that is sufficient to effectively treat or prevent AIDS. Such a composition would be useful for immunizing subjects chronically infected with human immunodeficiency virus-1 (HIV-1), symptomatic or asymptomatic, to minimize progression to AIDS (therapeutic composition), and also for immunizing non-infected subjects to prevent the establishment of chronic viremia and AIDS following subsequent HIV-1 infection (prophylactic immunization). The unmet need in this art is to provide a therapeutic or prophylactic composition that presents variants of Tat Epitope 1 in a manner sufficient to obtain an induced antibody titer against multiple Tat Epitope 1 variants (and thus multiple HIV-1 strains and subtypes) and which titer is sufficiently high to avoid the need for frequent, repeated re-administrations of the composition.